Sphingomyelin phosphodiesterase 4 (SMPD4) encodes a member of the Mg2+-dependent, neutral sphingomyelinase family that catalyzes the hydrolysis of the phosphodiester bond of sphingomyelin to form phosphorylcholine and ceramide. Recent studies have revealed that biallelic loss-of-function variants of SMPD4 cause syndromic neurodevelopmental disorders characterized by microcephaly, congenital arthrogryposis, and structural brain anomalies. In this study, three novel loss-of-function SMPD4 variants were identified using exome sequencing (ES) in two independent patients with developmental delays, microcephaly, seizures, and brain structural abnormalities. Patient 1 had a homozygous c.740_741del, p.(Val247Glufs*21) variant and showed profound intellectual disability, hepatomegaly, a simplified gyral pattern, and a thin corpus callosum without congenital dysmorphic features. Patient 2 had a compound heterozygous nonsense c.2124_2125del, p.(Phe709*) variant and splice site c.1188+2dup variant. RNA analysis revealed that the c.1188+2dup variant caused exon 13 skipping, leading to a frameshift (p.Ala406Ser*6). In vitro transcription analysis using minigene system suggested that mRNA transcribed from mutant allele may be degraded by nonsense-mediated mRNA decay system. He exhibited diverse manifestations, including growth defects, muscle hypotonia, respiratory distress, arthrogryposis, insulin-dependent diabetes mellitus, sensorineural hearing loss, facial dysmorphism, and various brain abnormalities, including cerebral atrophy, hypomyelination, and cerebellar hypoplasia. Here, we review previous literatures and discuss the phenotypic diversity of SMPD4-related disorders.
{"title":"Two novel cases of biallelic SMPD4 variants with brain structural abnormalities.","authors":"Shintaro Aoki, Kazuki Watanabe, Mitsuhiro Kato, Yukihiko Konishi, Kazuo Kubota, Emiko Kobayashi, Mitsuko Nakashima, Hirotomo Saitsu","doi":"10.1007/s10048-023-00737-5","DOIUrl":"10.1007/s10048-023-00737-5","url":null,"abstract":"<p><p>Sphingomyelin phosphodiesterase 4 (SMPD4) encodes a member of the Mg<sup>2+</sup>-dependent, neutral sphingomyelinase family that catalyzes the hydrolysis of the phosphodiester bond of sphingomyelin to form phosphorylcholine and ceramide. Recent studies have revealed that biallelic loss-of-function variants of SMPD4 cause syndromic neurodevelopmental disorders characterized by microcephaly, congenital arthrogryposis, and structural brain anomalies. In this study, three novel loss-of-function SMPD4 variants were identified using exome sequencing (ES) in two independent patients with developmental delays, microcephaly, seizures, and brain structural abnormalities. Patient 1 had a homozygous c.740_741del, p.(Val247Glufs*21) variant and showed profound intellectual disability, hepatomegaly, a simplified gyral pattern, and a thin corpus callosum without congenital dysmorphic features. Patient 2 had a compound heterozygous nonsense c.2124_2125del, p.(Phe709*) variant and splice site c.1188+2dup variant. RNA analysis revealed that the c.1188+2dup variant caused exon 13 skipping, leading to a frameshift (p.Ala406Ser*6). In vitro transcription analysis using minigene system suggested that mRNA transcribed from mutant allele may be degraded by nonsense-mediated mRNA decay system. He exhibited diverse manifestations, including growth defects, muscle hypotonia, respiratory distress, arthrogryposis, insulin-dependent diabetes mellitus, sensorineural hearing loss, facial dysmorphism, and various brain abnormalities, including cerebral atrophy, hypomyelination, and cerebellar hypoplasia. Here, we review previous literatures and discuss the phenotypic diversity of SMPD4-related disorders.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50163891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1007/s10048-024-00747-x
Geraldine Zimmer-Bensch
{"title":"Correction to: New Editors-in-Chief and future directions: a glimpse into the evolving future of Neurogenetics.","authors":"Geraldine Zimmer-Bensch","doi":"10.1007/s10048-024-00747-x","DOIUrl":"10.1007/s10048-024-00747-x","url":null,"abstract":"","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10890974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139522285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1007/s10048-023-00740-w
Geraldine Zimmer-Bensch
{"title":"New Editors-in-Chief and future directions: a glimpse into the evolving future of Neurogenetics.","authors":"Geraldine Zimmer-Bensch","doi":"10.1007/s10048-023-00740-w","DOIUrl":"10.1007/s10048-023-00740-w","url":null,"abstract":"","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10891218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139076042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-20DOI: 10.1007/s10048-023-00739-3
N. Gammaldi, S. Doccini, S. Bernardi, M. Marchese, M. Cecchini, R. Ceravolo, S. Rapposelli, GM. Ratto, S. Rocchiccioli, F. Pezzini, F. M. Santorelli
Neuronal ceroid lipofuscinosis (NCL) is an umbrella term referring to the most frequent childhood-onset neurodegenerative diseases, which are also the main cause of childhood dementia. Although the molecular mechanisms underlying the NCLs remain elusive, evidence is increasingly pointing to shared disease pathways and common clinical features across the disease forms. The characterization of pathological mechanisms, disease modifiers, and biomarkers might facilitate the development of treatment strategies.
The DEM-AGING project aims to define molecular signatures in NCL and expedite biomarker discovery with a view to identifying novel targets for monitoring disease status and progression and accelerating clinical trial readiness in this field. In this study, we fused multiomic assessments in established NCL models with similar data on the more common late-onset neurodegenerative conditions in order to test the hypothesis of shared molecular fingerprints critical to the underlying pathological mechanisms. Our aim, ultimately, is to combine data analysis, cell models, and omic strategies in an effort to trace new routes to therapies that might readily be applied in the most common forms of dementia.
{"title":"Dem-Aging: autophagy-related pathologies and the “two faces of dementia”","authors":"N. Gammaldi, S. Doccini, S. Bernardi, M. Marchese, M. Cecchini, R. Ceravolo, S. Rapposelli, GM. Ratto, S. Rocchiccioli, F. Pezzini, F. M. Santorelli","doi":"10.1007/s10048-023-00739-3","DOIUrl":"https://doi.org/10.1007/s10048-023-00739-3","url":null,"abstract":"<p>Neuronal ceroid lipofuscinosis (NCL) is an umbrella term referring to the most frequent childhood-onset neurodegenerative diseases, which are also the main cause of childhood dementia. Although the molecular mechanisms underlying the NCLs remain elusive, evidence is increasingly pointing to shared disease pathways and common clinical features across the disease forms. The characterization of pathological mechanisms, disease modifiers, and biomarkers might facilitate the development of treatment strategies.</p><p>The DEM-AGING project aims to define molecular signatures in NCL and expedite biomarker discovery with a view to identifying novel targets for monitoring disease status and progression and accelerating clinical trial readiness in this field. In this study, we fused multiomic assessments in established NCL models with similar data on the more common late-onset neurodegenerative conditions in order to test the hypothesis of shared molecular fingerprints critical to the underlying pathological mechanisms. Our aim, ultimately, is to combine data analysis, cell models, and omic strategies in an effort to trace new routes to therapies that might readily be applied in the most common forms of dementia.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138818851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-18DOI: 10.1007/s10048-023-00741-9
Stéphane Abramowicz, Alexandre Dentel, Maxime Chouraqui, Bahram Bodaghi, Sara Touhami
Typical retinitis pigmentosa (RP) may not be the only retinal phenotype encountered in ataxia with vitamin E deficiency (AVED). The following short case series describes a novel form of retinopathy in AVED. We describe two patients with AVED belonging to the same consanguineous sibship. Both presented an unusual retinopathy consisting of scattered, multifocal, nummular, hyperautofluorescent atrophic retinal patches. The retinopathy remained stable under vitamin E supplementation. We hypothesize these changes to be the result of arrested AVED-related RP following early supplementation with α-tocopherol acetate.
典型的视网膜色素变性(RP)可能不是共济失调伴维生素 E 缺乏症(AVED)患者唯一的视网膜表型。下面这组简短的病例描述了 AVED 视网膜病变的一种新形式。我们描述了两名同属近亲的 AVED 患者。这两名患者都出现了不寻常的视网膜病变,包括散在、多灶、麻木、高自发光的萎缩性视网膜斑块。在补充维生素 E 后,视网膜病变保持稳定。我们推测这些变化是在早期补充α-生育酚醋酸盐后,与 AVED 相关的 RP 被抑制的结果。
{"title":"Atypical retinopathy in ataxia with vitamin E deficiency: report of a sibship","authors":"Stéphane Abramowicz, Alexandre Dentel, Maxime Chouraqui, Bahram Bodaghi, Sara Touhami","doi":"10.1007/s10048-023-00741-9","DOIUrl":"https://doi.org/10.1007/s10048-023-00741-9","url":null,"abstract":"<p>Typical retinitis pigmentosa (RP) may not be the only retinal phenotype encountered in ataxia with vitamin E deficiency (AVED). The following short case series describes a novel form of retinopathy in AVED. We describe two patients with AVED belonging to the same consanguineous sibship. Both presented an unusual retinopathy consisting of scattered, multifocal, nummular, hyperautofluorescent atrophic retinal patches. The retinopathy remained stable under vitamin E supplementation. We hypothesize these changes to be the result of arrested AVED-related RP following early supplementation with α-tocopherol acetate.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138715216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-01Epub Date: 2023-08-17DOI: 10.1007/s10048-023-00728-6
Maike Tomforde, Meike Steinbach, Tobias B Haack, Gregor Kuhlenbäumer
Both, recessive (LGMD R1) and dominant (LGMD D4) inheritance occur in calpain 3-related muscular dystrophy. We report a family with calpain-related muscular dystrophy caused by two known variants in the calpain 3 gene (CAPN3, NM_000070.3; (I) c.700G>A, p.Gly234Arg and (II) c.1746-20C>G, p.?). Three family members are compound heterozygous and exhibit a relatively homogeneous phenotype characterized by progressive proximal weakness starting in the third to fourth decade of life in the shoulder girdle and spreading to the legs. Two family members affected only by the p.Gly234Arg heterozygous missense variants show a different phenotype characterized by severe exertional myalgia without overt pareses. We conclude that in our family, the missense variant causes a severe myalgic phenotype without pareses that is aggravated by the second intronic variant and put these findings in the context of previous studies of the same variants.
{"title":"Family and literature analysis demonstrates phenotypic effect of two variants in the calpain-3 gene.","authors":"Maike Tomforde, Meike Steinbach, Tobias B Haack, Gregor Kuhlenbäumer","doi":"10.1007/s10048-023-00728-6","DOIUrl":"10.1007/s10048-023-00728-6","url":null,"abstract":"<p><p>Both, recessive (LGMD R1) and dominant (LGMD D4) inheritance occur in calpain 3-related muscular dystrophy. We report a family with calpain-related muscular dystrophy caused by two known variants in the calpain 3 gene (CAPN3, NM_000070.3; (I) c.700G>A, p.Gly234Arg and (II) c.1746-20C>G, p.?). Three family members are compound heterozygous and exhibit a relatively homogeneous phenotype characterized by progressive proximal weakness starting in the third to fourth decade of life in the shoulder girdle and spreading to the legs. Two family members affected only by the p.Gly234Arg heterozygous missense variants show a different phenotype characterized by severe exertional myalgia without overt pareses. We conclude that in our family, the missense variant causes a severe myalgic phenotype without pareses that is aggravated by the second intronic variant and put these findings in the context of previous studies of the same variants.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10545561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10390337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-01Epub Date: 2023-07-31DOI: 10.1007/s10048-023-00727-7
Nana Li, Hong Kang, Yanna Zou, Zhen Liu, Ying Deng, Meixian Wang, Lu Li, Hong Qin, Xiaoqiong Qiu, Yanping Wang, Jun Zhu, Mark Agostino, Julian I-T Heng, Ping Yu
Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired adaptive behavior and cognitive capacity. High throughput sequencing approaches have revealed the genetic etiologies for 25-50% of ID patients, while inherited genetic mutations were detected in <5% cases. Here, we investigated the genetic cause for non-syndromic ID in a Han Chinese family. Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children, and their asymptomatic parents. Data was filtered for rare variants, and in silico prediction tools were used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. In silico modeling was used to evaluate the mutation's effects on the protein encoded by a candidate coding gene. A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts zinc binding within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. This is the first report of an inherited ZBTB18 mutation for ID. This study further validates WGS for the accurate molecular diagnosis of ID.
{"title":"A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability.","authors":"Nana Li, Hong Kang, Yanna Zou, Zhen Liu, Ying Deng, Meixian Wang, Lu Li, Hong Qin, Xiaoqiong Qiu, Yanping Wang, Jun Zhu, Mark Agostino, Julian I-T Heng, Ping Yu","doi":"10.1007/s10048-023-00727-7","DOIUrl":"10.1007/s10048-023-00727-7","url":null,"abstract":"<p><p>Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired adaptive behavior and cognitive capacity. High throughput sequencing approaches have revealed the genetic etiologies for 25-50% of ID patients, while inherited genetic mutations were detected in <5% cases. Here, we investigated the genetic cause for non-syndromic ID in a Han Chinese family. Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children, and their asymptomatic parents. Data was filtered for rare variants, and in silico prediction tools were used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. In silico modeling was used to evaluate the mutation's effects on the protein encoded by a candidate coding gene. A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts zinc binding within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. This is the first report of an inherited ZBTB18 mutation for ID. This study further validates WGS for the accurate molecular diagnosis of ID.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10268432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-01Epub Date: 2023-08-16DOI: 10.1007/s10048-023-00731-x
Yang You, Xinyi Men, Wenjuan Wu, Shan Liu, Xuexin He, Suzhen Sun, Xiuxia Wang, Baoguang Li
The cyclin-dependent kinase like 5 (CDKL5) gene variation is X-linked dominant and is associated with type 2 developmental and epileptic encephalopathy (DEE). Although numerous cases of CDKL5 have been reported, there is limited discussion regarding functional verification. We described two children with DEE caused by de novo variations of CDKL5 gene, analyzed their clinical manifestations, and performed genetic testing on their gene variation sites. The two cases presented with tonic seizures followed by epileptic spasms, indicative of refractory epilepsy. Physical examination revealed abnormal facial features, including wide eye distance, low nose base, and high nose bridge. Both cases exhibited developmental disabilities. Cranial magnetic resonance imaging (MRI) showed widening of the bilateral frontotemporal extracerebral space. Genetic testing identified variations at the gene sites c.463 + 4A > G (splicing) and c.1854_1861delCAAAGTGA (p.D618Efs*18). Minigene experiments further confirmed that the intronic variation c.463 + 4A > G (splicing) disrupted splicing, leading to protein truncation. CDKL5 gene variation can lead to DEE, and intron variation site c.463 + 4A > G (splicing) can cause protein truncation, which is a pathogenic variation.
{"title":"Clinical and functional study of two de novo variations of CDKL5 gene.","authors":"Yang You, Xinyi Men, Wenjuan Wu, Shan Liu, Xuexin He, Suzhen Sun, Xiuxia Wang, Baoguang Li","doi":"10.1007/s10048-023-00731-x","DOIUrl":"10.1007/s10048-023-00731-x","url":null,"abstract":"<p><p>The cyclin-dependent kinase like 5 (CDKL5) gene variation is X-linked dominant and is associated with type 2 developmental and epileptic encephalopathy (DEE). Although numerous cases of CDKL5 have been reported, there is limited discussion regarding functional verification. We described two children with DEE caused by de novo variations of CDKL5 gene, analyzed their clinical manifestations, and performed genetic testing on their gene variation sites. The two cases presented with tonic seizures followed by epileptic spasms, indicative of refractory epilepsy. Physical examination revealed abnormal facial features, including wide eye distance, low nose base, and high nose bridge. Both cases exhibited developmental disabilities. Cranial magnetic resonance imaging (MRI) showed widening of the bilateral frontotemporal extracerebral space. Genetic testing identified variations at the gene sites c.463 + 4A > G (splicing) and c.1854_1861delCAAAGTGA (p.D618Efs*18). Minigene experiments further confirmed that the intronic variation c.463 + 4A > G (splicing) disrupted splicing, leading to protein truncation. CDKL5 gene variation can lead to DEE, and intron variation site c.463 + 4A > G (splicing) can cause protein truncation, which is a pathogenic variation.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10004553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-01Epub Date: 2023-09-02DOI: 10.1007/s10048-023-00732-w
Saar Anis, Tsvia Fay-Karmon, Simon Lassman, Fadi Shbat, Orit Lesman-Segev, Nofar Mor, Ortal Barel, Dan Dominissini, Odelia Chorin, Elon Pras, Lior Greenbaum, Sharon Hassin-Baer
Alexander disease (AxD) is a rare autosomal dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acid protein (GFAP) gene. The age of symptoms onset ranges from infancy to adulthood, with variable clinical and radiological manifestations. Adult-onset AxD manifests as a chronic and progressive condition, characterized by bulbar, motor, cerebellar, and other clinical signs and symptoms. Neuroradiological findings typically involve the brainstem and cervical spinal cord. Adult-onset AxD has been described in diverse populations but is rare in Israel. We present a series of patients diagnosed with adult-onset AxD from three families, all of Jewish Syrian descent. Five patients (4 females) were diagnosed with adult-onset AxD due to the heterozygous mutation c.219G > A, p.Met73Ile in GFAP. Age at symptoms onset ranged from 48 to 61 years. Clinical characteristics were typical and involved progressive bulbar and gait disturbance, followed by pyramidal and cerebellar impairment, dysautonomia, and cognitive decline. Imaging findings included medullary and cervical spinal atrophy and mostly infratentorial white matter hyperintensities. A newly recognized cluster of adult-onset AxD in Jews of Syrian origin is presented. This disorder should be considered in differential diagnosis in appropriate circumstances. Genetic counselling for family members is required in order to discuss options for future family planning.
{"title":"Adult-onset Alexander disease among patients of Jewish Syrian descent.","authors":"Saar Anis, Tsvia Fay-Karmon, Simon Lassman, Fadi Shbat, Orit Lesman-Segev, Nofar Mor, Ortal Barel, Dan Dominissini, Odelia Chorin, Elon Pras, Lior Greenbaum, Sharon Hassin-Baer","doi":"10.1007/s10048-023-00732-w","DOIUrl":"10.1007/s10048-023-00732-w","url":null,"abstract":"<p><p>Alexander disease (AxD) is a rare autosomal dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acid protein (GFAP) gene. The age of symptoms onset ranges from infancy to adulthood, with variable clinical and radiological manifestations. Adult-onset AxD manifests as a chronic and progressive condition, characterized by bulbar, motor, cerebellar, and other clinical signs and symptoms. Neuroradiological findings typically involve the brainstem and cervical spinal cord. Adult-onset AxD has been described in diverse populations but is rare in Israel. We present a series of patients diagnosed with adult-onset AxD from three families, all of Jewish Syrian descent. Five patients (4 females) were diagnosed with adult-onset AxD due to the heterozygous mutation c.219G > A, p.Met73Ile in GFAP. Age at symptoms onset ranged from 48 to 61 years. Clinical characteristics were typical and involved progressive bulbar and gait disturbance, followed by pyramidal and cerebellar impairment, dysautonomia, and cognitive decline. Imaging findings included medullary and cervical spinal atrophy and mostly infratentorial white matter hyperintensities. A newly recognized cluster of adult-onset AxD in Jews of Syrian origin is presented. This disorder should be considered in differential diagnosis in appropriate circumstances. Genetic counselling for family members is required in order to discuss options for future family planning.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10511523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}